The over-65 population is not only increasing at an alarming rate, but because six out of 10 will be managing more than one chronic condition by 2030, they will make up a much greater proportion of hospitalizations than ever before. Hospitalizations for disease, injury, and/or surgery in this group are likely to impair physical mobility and, therefore, the older adults capacity to be physically active both during hospitalization and beyond. The resulting sedentary lifestyle is likely to be accepted as the new normal, ultimately increasing the risk of skeletal muscle and metabolic dysfunction (e.g. impaired glucose disposal, insulin resistance). These devastating outcomes are neither inevitable nor necessary if prevented with an appropriate mechanism-based intervention. A novel mechanism that may contribute to physical inactivity-induced insulin resistance is accumulation of inflammation and ceramide within skeletal muscle initiated by activation of the toll-like receptor 4 (TLR4)/MyD88 signaling pathway. We have previously shown that skeletal muscle TLR4/MyD88 signaling regulates pro-inflammatory pathways and ceramide biosynthesis whereas knockdown of TLR4 protects muscle against lipid-induced insulin resistance. Of interest, increased skeletal muscle TLR4, inflammation and ceramide has been tied to various metabolic disturbances such as diabetes and insulin resistance. However, it is currently unknown if skeletal muscle TLR4/MyD88 signaling and the subsequent increase in inflammation and ceramide are a key mechanism associated with insulin resistance due to physical inactivity in older adults. Dr. Drummond's preliminary work supports the hypothesis that physical inactivity increases TLR4, inflammation, and ceramide biosynthesis in skeletal muscle of older adults. Additionally, our preliminary data in mouse experiments indicate that MyD88 signaling is necessary for reduced insulin sensitivity caused by short- term physical inactivity. Therefore, Dr. Drummond and his multidisciplinary research team have proposed to conduct parallel clinical studies in older adults and a series of mechanistic studies using muscle-specific mouse models and drug intervention studies to test whether skeletal muscle TLR4/MyD88 signaling is important in the production of inflammation and ceramide and therefore insulin resistance caused by physical inactivity. These findings will be foundational for developing treatments to prevent insulin resistance in inactive older adults.